Page 18 - Advanced Organic Chemistry Part B - Reactions & Synthesis

xix
1
R O O OH CH 3 CO 2 O OH Introduction
Ph O
2
R NH O H O HO H O
OH HO OBz OAc HO OBz OAc
2
taxol R = Ac, R = PhCO baccatin III
1
Macrocyclic antibiotics such as the erythronolide present an additional challenge.

O
CH 3 CH 3
HO OH
OH
CH 3 CH 3 CH 3
C H O OH
2 5
O OH
CH 3
erythronolide

These molecules contain many stereogenic centers and they are generally
constructed from acyclic segments, so the ability to control configuration in acyclic
systems is necessary. Solutions to this problem developed beginning in the 1960s
are based on analysis of transition structures and the concepts of cyclic transition
structure and facial selectivity. The effect of nearby stereogenic centers has been
studied carefully and resulted in concepts such as the Felkin model for carbonyl
addition reactions and Cram’s model of chelation control. In Chapter 13, several
syntheses of epothilone A, a 16-membered lactone that has antitumor activity, are
summarized. The syntheses illustrate methods for both acyclic stereochemical control
and macrocyclization, including the application of the olefin metathesis reaction.

O
S
12
13
HO N
17
5 3 1 O
O OH O
Epothilone A

We also discuss the synthesis of + -discodermolide, a potent antitumor agent
isolated from a deep-water sponge in the Caribbean Sea. The first synthesis was
reported in the mid-1990s, and synthetic activity is ongoing. Discodermolide is
a good example of the capability of current synthetic methodology to produce
complex molecules. The molecule contains a 24-carbon chain with a single lactone
ring connecting C(1) and C(5). There are eight methyl substituents and six oxygen
substituents, one of which is carbamoylated. The chain ends with a diene unit. By
combining and refining elements of several earlier syntheses, it was possible to carry